This renewal application for a K24 Midcareer Investigator Award in Patient-Oriented Research is intended to promote mentoring activities and career development focused on studies of the effects of aging on the human immune system. Notably, no other currently funded K24 at the NIA is devoted to translational immunology. The PI, Dr. Shaw, is Associate Professor of Medicine at the Yale School of Medicine; he is trained in Internal Medicine and Infectious Disease, and in addition has a Ph.D. in Genetics and is a trained immunologist. Dr. Shaw is recognized as an authority on the aging of the human immune system; his lab has a special interest in aging of the innate immune system, and has carried out the largest and most comprehensive studies to date of the consequences of aging on human Toll-like Receptor (TLR) function. In addition, his group has advanced understanding of the effects of age on cellular and gene expression signatures of influenza vaccine response. Dr. Shaw is the Project Leader of an R01 within a competitively renewed U19 Center Grant based at Yale that is part of the NIH Human Immunology Project Consortium. This project will elucidate immunologic, gene expression, and metabolomic signatures of high-dose influenza vaccine response in young, frail and non-frail older adults. Dr. Shaw is also a PI of a new R01 from the NIA focusing on influenza vaccine response in the context of aging and HIV infection. These two initiatives form the platform for the mentoring and career development plan directed to developing new investigators studying the immunology of aging. In addition, a pilot study based on the HIV/aging R01 is proposed to elucidate metabolomics and metabolic profiling signatures of vaccine response. This research platform will be supported by career development activities for the PI that include tutorials in computational biology and gerontologic biostatistics. Dr. Shaw is a PI of the T32- supported research training program for the Section of Infectious Diseases at Yale, and is the Leader of the Pilot and Exploratory Studies Core and Co-Director of the Research Education Core of the Yale Pepper Center, mentoring activities that are concurrent elements within the K24 program. As a result, Dr. Shaw has an unparalleled view of laboratory based aging research at Yale to enhance mentee research training and career development of junior investigators. During the first funding period of this award, Dr. Shaw?s mentees have been highly successful, including NIA GEMSSTAR and Beeson Scholar awardees, and the K24 program was instrumental in the expansion of NIH grant support to Dr. Shaw. The proposed program will further enhance the PI?s ongoing role as a mentor to the next generation of investigators who will advance our understanding of human immunology in the context of aging. !